A long-acting octreotide analog formed by conjugation with a peptide linker modified with two fatty acids

Current long-acting somatostatin analogs control acromegaly and neuroendocrine tumor symptoms, but rely on depot formulations requiring large-bore needle administration, often associated with injection-site pain, nodules, and variable drug release. To address this limitation, we developed TE-8214, a depot-free octreotide analog conjugated to a soluble, dual-fatty-acid albumin-binding module designed to enable prolonged systemic exposure while maintaining a fully aqueous formulation suitable for subcutaneous administration through a fine 30-gauge needle.

TE-8214's binding to human serum albumin (HSA) and somatostatin receptor 2 (SSTR2), and its receptor-mediated functional activity, were characterized in vitro and compared with octreotide. Pharmacokinetics and pharmacodynamics - suppression of serotonin, growth hormone, and insulin-like growth factor-1 (IGF-1) - were assessed in rodents and dogs following single or repeated dosing of TE-8214 or equimolar octreotide. Safety, tolerability, and pharmacokinetics of TE-8214 were then evaluated in a randomized, double-blind, placebo-controlled Phase 1 single-ascending-dose study in healthy adults (0.6-4.0 mg), with IGF-1 assessed as an exploratory pharmacodynamic biomarker.

In vitro, TE-8214 bound HSA while retaining potent SSTR2-mediated activity comparable to octreotide. In rodents and dogs, TE-8214's albumin binding extended its terminal half-life and enabled sustained suppression of serotonin, growth hormone, and IGF-1, exceeding the duration achieved with equimolar octreotide. In the Phase 1 study, TE-8214 was well-tolerated across all doses tested, with no serious or Grade ≥3 treatment-emergent adverse events, and produced sustained, dose-dependent reductions in IGF-1 consistent with systemic exposure; at the highest dose, IGF-1 fell by 22.5% from baseline and remained suppressed through Day 28.

These findings demonstrate that a depot-free, aqueous-formulated octreotide analog can achieve prolonged systemic exposure and sustained pharmacodynamic activity following a single dose in healthy volunteers. Although this study was not designed to evaluate therapeutic efficacy, the pharmacokinetic and pharmacodynamic profile of TE-8214 supports further clinical evaluation in patients with neuroendocrine tumors or acromegaly.

https://clinicaltrials.gov/, identifier NCT06372652.